1. Field of the Invention
This invention relates generally to the field of phosphorus chemistry, and is particularly concerned with a novel method for the production of .alpha.-keto bisphosphonate esters (carbonylbisphosphonate esters) and the use of these esters in reactions with C, N, O, or P nucleophiles for synthesis of .alpha.-functionalized bisphosphonates.
2. Description of Related Art
There are several pathological conditions that involve irregularities in calcium and phosphate metabolism. Such conditions comprise bone related diseases including Paget's disease and osteoporosis, as well as osteolysis in bone metastases. Bone metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important complication of malignancy, causing distressful symptoms, such as severe pain and spontaneous fractures, and may lead to a metabolic coma and death. Moreover, neoplastic cell-induced osteolysis may determine the localization and growth enhancement of bone tumors. (See, G. R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987); and Calcium in Biological Systems, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. eds. Plenum Press, N.Y. (1985). Other pathological conditions cause or result from deposition of calcium and phosphate anomalously in the body, such as rheumatoid arthritis and osteoarthritis.
In some common bone disorders, the balance between the process of resorption and formation remains normal, but the rate of bone turnover is much higher. Most cases of primary hyperparathyroidism, Paget's disease, and thyroxicosis are in this category. In other common diseases such as osteoporosis, there is an imbalance between resorption and formation. Whether increased resorption or impaired formation predominates, however, the consequence is the same, i.e., diminished total bone mass.
Natural pyrophosphates having the structure: ##STR1## are known to be natural regulators of Ca.sup.2+ metabolism at the cellular level. In recent years, many investigators have shown interest in the method of synthesis and biological activity of synthetic analogs of pyrophosphates, namely bisphosphonates and their derivatives. Bisphosphonic acids having the structure: ##STR2## and their derivatives are pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon.
Bisphosphonates are a class of drugs that have been developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification. (M. D. Francis and R. R. Martodam, "The Role of Phosphonates in Living Systems" R. L. Hilderbrand, ed., CRC Press, Boca Raton, Fla., 1983, pp. 55-96; and H. Fleisch, Bone, 1987, 8, Supp. 1, S23-S28). A current theory attributes the biological activity of anti-resorptive bisphosphonates to two design components. One of these components is the so-called "bone-hook" functionality, associated with the bisphosphonate backbone, which is all of the molecule except the R group substituent in the following formula (3): [(HO).sub.2 P(O)CR(OH)P(O)(OH).sub.2 ]. This bone-hook functionality is directly responsible for primary hydroxyapatite adsorption. The second design component is the bioactive moiety, R group, which is postulated to modulate the anti-resorptive potency of the drug within a given affinity class. See, Ebetino, F. H., Dansereau, S. M., Bisphosphonate on Bones; Bijvoet, O., Fleisch, H. A., Canfield, R. E., Russell, G., Eds. Elsevier Science B. V. 1995, p. 139-153. Numerous references disclose compositions containing polyphosphonates, in particular bisphosphonates, such as 1-hydroxyethylidenediphosphonic acid (HEDP) having the formula: (HO).sub.2 P(O)CCH.sub.3 (OH)P(O)(OH).sub.2, where the R group in (3) is CH.sub.3. See, U.S. Pat. Nos. 3,683,080 and 4,230,700 to Francis. See also, U.S. Pat. No. 4,868,164 to Ebetino, et al., which refers to heterocyclic bisphosphonates. HEDP is used in medicine under the name Etidronate (disodium salt of HEDP). HEDP is a useful complexing agent for alkaline earth, transition, and lanthanide metals. HEDP is also used to regulate calcium metabolism in the treatment of Paget's disease, to inhibit formation and growth of calcium oxalate stones in kidneys, and to reduce plaque when added to dental preparations. HEDP has also been suggested for use in treatment of diseases ranging from bone cancer to arthritis (See, Zolotukhina, et al., Russian Chemical Reviews, 1993, 62, 647-659). Numerous other references describe bisphosphonic acids useful for the treatment of osteoporosis and/or arthritis, and are herein incorporated by reference: U.S. Pat. No. 5,104,863 to Benedict, et al.; U.S. Pat. No. 4,267,108 to Blum, et al.; U.S. Pat. No. 4,754,993, to Bosies, et al.; U.S. Pat. No. 4,939,130 to Jaeggi, et al.; U.S. Pat. No. 4,971,958 to Bosies, et al.; DE 40 11 777 to Jaeggi; WO 90/12017 to Dunn, et al.; WP 91/10646 to Youssefyeh, et al.; AU-A-26738/88 to Jaeggi; AU-A-45467/89, assigned to Ciba-Geigy; and U.S. Pat. No. 4,208,401 to Bauman.
The elucidation and further development of structure-activity relationships in the bisphosphonate class of compounds has increasingly flourished during the past few years (See, Ebetino, F. H., et al., supra; and Zolotukhina, et al., supra.) Rational design of new medicinal agents based on bisphosphonates has progressed from simple .alpha.-alkyl and .alpha.-halo bisphosphonates, to bisphosphonates substituted with a range of heterocyclic and heteroatomic moieties. Bisphosphonate chemistry has yielded an increasing variety of bone-active compounds, including potent anti-resorptive agents that have therapeutic potential in osteoporosis and other diseases of bone metabolism (See, Ebetino, F. H., et al., supra.) Variation in the P-C-P backbone has led to analogs of varied hydroxyapatite affinity, Ca.sup.2+ chelation and anti-mineralization properties.
McKenna, et al., have reported the synthesis of crude carbonylbisphosphonate ester preparations by reaction of the corresponding .alpha.-diazo compounds with tert-butyl hypochlorite in formic acid, followed by a second step of pyrolytic distillation at reduced pressure. (See, McKenna, C. E.; Khare, A.; Ju, J. -Y.; Li, Z. -M.; Duncan, G.; Cheng, Y. -C.; Kilkuskie, R. Phosphorus Sulfur, 76:139-142, 1993). However, this method of synthesis suffers from serious defects: 1) The carbonylbisphosphonate esters are obtained in moderate to poor, erratic, yields, particularly due to the instability of the reaction mixture to prolonged heating; 2) An undesirable .alpha.-dichlorinated side product is usually formed, which resists attempts at removal; 3) Other impurities are often present, seen by NMR analysis. Furthermore, the vacuum pyrolysis in the second step is difficult to control and is difficult to scale up.
It has also been reported that reaction of carbanion nucleophiles such as Reformatsky reagents with .alpha.-keto monophosphonates (4) leads not to the desired .alpha.-hydroxy .alpha.-alkylated adduct (5) of the present invention, but instead to elimination of the phosphorus moiety forming a carbonyl product (6) and phosphite (7) (See, Breuer, E., The Chemistry of Organophosphorus Compounds; Hartley, F. R., Ed.; John Wiley & Sons: New York, (1996) Vol. 4: 653-730, p.685.) ##STR3##
Hydrates of the impure carbonylbisphosphonate esters, prepared by the previous method of McKenna, et al., are readily formed by treatment with H.sub.2 O, however, the hydrates were not isolated. (See, McKenna, et al., supra.) Prior to the present invention, attempts to regenerate pure carbonylbisphosphonate esters, free of the .alpha.,.alpha.-dichloro contaminant and other impurities, have been unsuccessful. For example, in the previous method of McKenna, et al., the regeneration of carbonylbisphosphonate esters by evaporation (via heating and low pressure) of the aqueous phase, after extraction with an organic solvent, lead instead to formation of an unwanted product containing both phosphonate and phosphate groups.
It was previously reported that vicinal trioxo compounds can be obtained from corresponding .alpha.-diazo compounds through an "oxygen-halogen-insertion" reaction using t-BuOCl in formic acid, acetonitrile and other solvents (See, Regitz, M.; Adolph, H. -G. Liebigs Ann. Chem. 1969, 723, 47-60.) Regitz, et al., proposed that chloro-tertbutyloxy-diacylmethanes are first formed, which decompose spontaneously into tertbutyl chloride and the trioxo product. As described above, an analogous approach led to the synthesis of crude carbonylbisphosphonate esters. (See, McKenna, et al., Phosphorus Sulfur, (1993), supra). The unsatisfactory nature of this method was initially ascribed to inadequate drying of the solvent, or non-optimal solvent. However, reactions carried out according to the previous procedure of McKenna, et al., between diazo MDP esters and t-BuOCl in different, very well-dried solvents, such as: acetonitrile; acetone; ethyl acetate; t-butanol; and CCl.sub.4, still gave low yields of the desired products and was accompanied by the usual formation of unwanted side products, including .alpha.,.alpha.-dichlorinated bisphosphonate. (See, McKenna, et al., supra.) The intermediate product expected to be formed in the first step of this procedure, .alpha.-chloro-.alpha.-alkoxy methylenebisphosphonate, did not decompose spontaneously into the oxo product (.sup.31 P NMR evidence), and thus required pyrolysis.
Regitz, et al., postulated that interaction between 2-diazo 1,3-oxo compounds and t-butylhypochlorite in alcohols involves intermediate formation of an .alpha.-diazonium .alpha.-chloro bisphosphonate species and a t-butoxide anion, followed by nucleophilic substitution of the --N.sub.2.sup.+ leaving group by an alcohol molecule (S.sub.N 2 or S.sub.N 1)(See, Regitz, et al., supra.) However, according to this mechanism, the first step, the formation of the .alpha.-diazonium .alpha.-chloro species and t-butoxide anion, requires release of t-butoxide, a very poor leaving group.
Generally, for efficient transfer of positive chlorine from alkylhypochlorite, an activated species, such as the protonated form of the alkoxide, is desirable as the leaving group. (See, Tassignon, P. S. G., et al., (1995) Tetrahedron Lett., Vol. 43: p.11 863-11 872). Thus, t-butanol is a more reasonable leaving group in this reaction than t-butoxide. In formic acid the solvent provides a proton, but also the wrong nucleophile for carbonylbisphosphonate ester formation, which then must be removed in the inefficient pyrolysis step. The substitution taking place in the second step of this reaction, between the .alpha.-diazonium .alpha.-chloro bisphosphonate species and a nucleophile, therefore requires a nucleophile able to produce an intermediate that facilely leads to the desired carbonylbisphosphonate ester. Consequently, it appears there is a need for a better nucleophile for this reaction. Moreover, .alpha.-hydroxy bisphosphonates possess high affinity for hydroxyapatite and can be highly potent anti-resorptive agents, thus chemistry that generates a methylenebisphosphonate with an .alpha.-hydroxy function together with the addition of a R group is particularly desirable.
There continues to be a need for new bone-active agents. Design and synthesis of new bisphosphonates active against bone diseases would be greatly aided by preparative methodology facilitating introduction of the R moiety into the bisphosphonate structure. Such methodology, could also be employed for preparation of bisphosphonates that would be useful in treating many bone and other diseases, such as viral infections, or other health disorders that may be responsive to phosphonate drugs. (See, Zolotukhina, et al., supra.) Indeed, methodology facilitating introduction of a R group moiety into the bisphosphonate structure could be used to prepare any bisphosphonate possessing a particular utility or desirable property requiring introduction of a specific R group.